The neuropeptide receptor for Neurokinin 1 (substance P, NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue. The receptor for substance P is a member of the superfamily of G protein-coupled receptors.
The central and peripheral actions of the mammalian tachykinin, substance P, have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson""s disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer""s disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn""s disease, ocular injury and ocular inflammatory diseases is reviewed in xe2x80x9cTachykinin Receptor and Tachykinin Receptor Antagonistsxe2x80x9d, J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin-1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, in The New England Journal of Medicine, Vol. 340, No. 3 190-195, 1999 has been described the reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist.
Furthermore, U.S. Pat. No. 5,972,938 describes a method for treating a psychoimmunologic or a psychosomatic disorder by administration of a tachykinin receptor, such as NK-1 receptor antagonist.
In accordance with the present invention, the compounds of formula I and their salts are characterized by valuable therapeutic properties. It has been surprisingly found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Objects of the present invention are the compounds of formula I and pharmaceutically acceptable salts thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier or in the manufacture of corresponding medicaments. The most preferred indications for treatment in accordance with the present invention are those which include disorders of the central nervous system or emesis, for example the treatment or prevention of certain depressive disorders by the administration of NK-1 receptor antagonists. A major depressive episode has been defined as being a period of at least two weeks during which, for most of the day and nearly every day, there is either depressed mood or the loss of interest or pleasure in all, or nearly all activities.
The present invention relates to compounds of the general formula 
wherein
R is hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
R1 is hydrogen or halogen; or
R and R1 may be together xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94;
R2 is hydrogen, halogen, trifluoromethyl, lower alkoxy or cyano;
R3 is, independently from each other, hydrogen, lower alkyl or form a cycloalkyl group;
R4 is hydrogen, halogen, lower alkyl, lower alkoxy, xe2x80x94N(R5)2, xe2x80x94N(R5)S(O)2-lower alkyl, xe2x80x94N(R5)C(O)R5 or a cyclic tertiary amine of the group 
R5 is, independently from each other, hydrogen, C3-6-cycloalkyl, benzyl or lower alkyl;
R6 is hydrogen, hydroxy, lower alkyl, xe2x80x94N(R5)CO-lower alkyl, hydroxy-lower alkyl, cyano, xe2x80x94CHO or a 5- or 6 membered heterocyclic group, optionally bonded via an alkylene group,
X is xe2x80x94C(O)N(R5)xe2x80x94, xe2x80x94(CH2)mOxe2x80x94, xe2x80x94(CH2)mN(R5)xe2x80x94, xe2x80x94N(R5)C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94N(R5)(CH2)mxe2x80x94;
Y is xe2x80x94(CH2)nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94N(R5 )xe2x80x94;
Z is xe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90 or xe2x80x94C(O)xe2x95x90;
n is 0-4; and
m is 1 or 2;
and to pharmaceutically acceptable acid addition salts thereof.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a straight- or branched-chain alkyl group containing from 1-7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues are as defined above, and which is attached via an oxygen atom.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated carbocyclic group, containing 3-6 carbon atoms.
The term xe2x80x9ccyclic tertiary aminexe2x80x9d denotes, for example, pyrrol-1-yl, imidazol-1-yl, piperidin-1-yl, piperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl.
The term xe2x80x9c5 or 6 membered heterocyclic groupxe2x80x9d denotes, for example pyridinyl, pyrimidinyl, oxadiazolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, piperazinyl or piperidyl.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
Exemplary preferred are compounds, in which Y is xe2x80x94C(O)xe2x80x94 and R4 is 4-methylpiperazinyl, for example the following compounds:
N-[2-Benzoyl-4-(4-methyl-piperazin-1-yl)-phenyl]-2-(3,5-bis-trifluoromethyl-phenyl)isobutyramide,
4-Benzoyl-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-(4-methyl-piperazin-1-yl) nicotinamide and
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-benzoyl)-N-methyl-6-(4-methyl-piperazin-1-yl)nicotinamide.
Further preferred are compounds, in which Y is xe2x80x94Oxe2x80x94 and R4 is hydrogen, morpholinyl or 4-methylpiperazinyl. Examples of such compounds are:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenoxy-phenyl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(2-o-tolyloxy-phenyl)-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(2,4-dichloro-phenoxy)-phenyl]-N-methyl-isobutyramide,
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-phenoxy-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-morpholin-4-yl-nicotinamide,
N-(3,5-Bis-trifluoromethyl-benzyl)-4-(2-chloro-phenoxy)-N-methyl-6-(4-methyl-piperazin-1-yl)-nicotinamide and
N-(3,5-Bis-trifluoromethyl-benzyl)-N-methyl-6-morpholin-4-yl-4-o-tolyloxy-nicotinamide.
Further preferred are compounds, in which Y is xe2x80x94N(CH3)xe2x80x94 and R4 is hydrogen, for example the following compounds:
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-isobutyramide,
2-(3,5-Bis-trifluoromethyl-phenyl)-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide and
2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-acetamide.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein R1-R5, R Y, Z and n have the significances given above, or
b) reacting a compound of formula 
with a compound of formula 
to give a compound of formula 
wherein R1-R5, R, Z, Y and n have the significances given above, or
c) reducing a compound of formula 
to a compound of formula 
wherein the definitions of substituents are given above, or
d) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the definitions of substituents are given above, or
e) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the definitions of substituents are given above, or
f) reducing a compound of formula 
to a compound of formula 
wherein the definitions of substituents are given above, or
g) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the definition of substituents is given above, or
h) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the definition of substituents is given above, or
i) reacting a compound of formula 
with a compound of formula 
to a compound of formula 
wherein the definition of substituents is given above, or
j) modifying one or more substituents R1-R5 or R within the definitions given above, and if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.
In accordance with process variant a) a compound of formula II, for example 3-amino-4-benzoylpyridine, is cooled in an ice bath and a compound of formula III, for example 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl propionyl chloride in the presence of DIPEA (N-ethyldiisopropyl-amine) in dichloromethane is added, and then the mixture is stirred at room temperature. The desired compound of formula I-1 is yielded after purification in good yields.
Process variant b) describes the reaction of a compound of formula IV with a compound of formula V to a compound of formula I-2. The reaction is carried out in conventional manner, for example in a solvent, such as a mixture of toluene and triethyl-amine. The mixture is refluxed for about 1 hour.
In accordance with process variant c) a compound of formula I-2 is reduced to a compound of formula I-4. This reaction is carried out with a reducing agent, such as LiAlH4 or BH3xe2x80xa2THF, in conventional manner.
Process variant d) describes the reaction of a compound of formula VI with a compound of formula VII to a compound of formula I-2. This reaction is carried out by deprotonation of a compound of formula VI with KHMDS (potassium hexamethyldisilazide) and subsequent addition of a compound of formula VII. A suitable solvent is tetra-hydrofuran. The reaction is carried out at room temperature.
In accordance with process variant e) a compound of formula I-5 is prepared. This reaction is carried out by deprotonation of a compound of formula VIII with NaH and subsequent addition of a compound of formula VII. This reaction is carried out in conventional manner.
A further method for the preparation of a compound of formula I is described in process variant f). A compound of formula I-1 is reduced to a compound of formula I-3 in conventional manner, for example with LiAlH4 or BH3xe2x80xa2THF.
In the process variant g) a compound of formula IX is activated with DCC (N,Nxe2x80x2-dicyclohexylcarbodiimide) and DMAP (4-N,N-dimethylaminopyridine). Subsequent addition of a compound of formula X yields a compound of formula I-6.
In accordance with variant h) a compound of formula IX is activated with CDI (1,1xe2x80x2-carbonyldiimidazole) and subsequent addition of a compound of formula V gives a compound of formula I-2.
The process variant i) describes the process for preparation of a compound of formula I-1, wherein a compound of formula XII is activated with CDI and subsequent addition of a compound of formula II yields a compound of formula I-13.
The salt formation is effected at room temperature in accordance with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids came into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methansulphonates, p-toluenesulphonates and the like are examples of such salts.
The following schemes 1-7 describe the processes for preparation of compounds of formula I in more detail. The starting materials of formulae IX, X, XI, II, III, XII, XIII,XV, XVII, XVIII, XX, XXII, X and XXV are known compounds or may be prepared according to methods known in the art.
In the schemes the following abbreviations have been used:

The substituents are given above. 
The substituents is given above. 
The definition of substituents is given above. 
The definition of substituents is given above. 
The definition of substituents is given above. 
The definition of substituents is given above 
R, R1, R2, R3 and R5 have the significances given above.
As mentioned earlier, the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. It has been found that the compounds of the present invention are antagonists of the Neurokinin 1 (NK-1, substance P) receptor.
The compounds were investigated in accordance with the tests given hereinafter.
The affinity of test compounds for the NK1 receptor was evaluated at human NK1 receptors in CHO cells infected with the human NK1 receptor (using the Semliki virus expression system) and radiolabelled with [3H] substance P (final concentration 0.6 nM). Binding assays were performed in HEPES buffer (50 mM, pH 7.4) containing BSA (0.04%) leupeptin (8 mg/ml), MnCl2 (3 mM) and phosphoramidon (2 mM). Binding assays consisted of 250 ml of membrane suspension (1.25xc3x97105 cells/assay tube), 0.125 ml of buffer of displacing agent and 125 ml of [3H]substance P. Displacement curves were determined with at least seven concentrations of the compound. The assay tubes were incubated for 60 min at room temperature after which time the tube contents were rapidly filtered under vacuum through GF/C filters presoaked for 60 min with PEI (0.3%) with 2xc3x972 ml washed of HEPES buffer (50 mM, pH 7.4). The radioactivity retained on the filters was measured by scintillation counting. All assays were performed in triplicate in at least 2 separate experiments.
The affinity to the NK-1 receptor, given as pKi, is in the scope of 7,50-9,00 for the preferred compounds. Examples for such compounds are
The compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragxc3xa9es, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
The compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragxc3xa9es and hard gelatine capsules. Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when necessary.